The primary goal for the proposed project period is to test the hypothesis that local anesthetics may modulate neuronal excitability by acting on cyclic nucleotide regulation of potassium channels. It has been recognized for some time that local anesthetics can depress the level of cyclic AMP in tissues and the enzymatic substrates for cyclic nucleotide production and degradation exist in myelinated nerve. In preliminary studies we have shown that exogenously applied and endogenously generated cyclic AMP enhance potassium currents in myelinated nerve and prolong the refractory period, and that isoproterenol, a beta-agonist, mimics the effect of cyclin AMP. These are new and unexpected findings in peripheral myelinated nerve; they suggest that cyclic nucleotides play a physiological role in modulating impulse traffic in axons. There are three specific aims proposed: 1. To quantify the effects of cyclic nucleotides on ionic channels in voltage-clamp studies on myelinated axons. 2. To examine the implications of cyclic nucleotide channel modulation for axon excitability, in studies of whole nerves and single axons using both intracellular and extracellular recording techniques. 3. To test whether local anesthetics, acting on the cyclic nucleotide mechanisms of potassium channel regulation, can change neuronal excitability in a way that may be related to their neurotoxic (convulsant) effects or to their anticonvulsant and antiarrhythmic properties. The proposed studies and the preliminary work on which they are based have been developed during the tenure of a grant, whose aims were primarily directed at a comparative study of local anesthetic effects on sodium channels. They thus represent a change in direction of an ongoing series of studies on local anesthetic behavior.